A competency framework on simulation modelling-supported decision-making for Master of Public Health graduates.

BACKGROUND: Simulation models are increasingly important for supporting decision-making in public health. However, due to lack of training, many public health professionals remain unfamiliar with constructing simulation models and using their outputs for decision-making. This study contributes to filling this gap by developing a competency framework on simulation model-supported decision-making targeting Master of Public Health education. METHODS: The study combined a literature review, a two-stage online Delphi survey and an online consensus workshop. A draft competency framework was developed based on 28 peer-reviewed publications. A two-stage online Delphi survey involving 15 experts was conducted to refine the framework. Finally, an online consensus workshop, including six experts, evaluated the competency framework and discussed its implementation. RESULTS: The competency framework identified 20 competencies related to stakeholder engagement, problem definition, evidence identification, participatory system mapping, model creation and calibration and the interpretation and dissemination of model results. The expert evaluation recommended differentiating professional profiles and levels of expertise and synergizing with existing course contents to support its implementation. CONCLUSIONS: The competency framework developed in this study is instrumental to including simulation model-supported decision-making in public health training. Future research is required to differentiate expertise levels and develop implementation strategies.

Improving Estimates of Social Contact Patterns for Airborne Transmission of Respiratory Pathogens.

Data on social contact patterns are widely used to parameterize age-mixing matrices in mathematical models of infectious diseases. Most studies focus on close contacts only (i.e., persons spoken with face-to-face). This focus may be appropriate for studies of droplet and short-range aerosol transmission but neglects casual or shared air contacts, who may be at risk from airborne transmission. Using data from 2 provinces in South Africa, we estimated age mixing patterns relevant for droplet transmission, nonsaturating airborne transmission, and Mycobacterium tuberculosis transmission, an airborne infection where saturation of household contacts occurs. Estimated contact patterns by age did not vary greatly between the infection types, indicating that widespread use of close contact data may not be resulting in major inaccuracies. However, contact in persons >50 years of age was lower when we considered casual contacts, and therefore the contribution of older age groups to airborne transmission may be overestimated.

Dynamics of sputum conversion during effective tuberculosis treatment: A systematic review and meta-analysis.

BACKGROUND: Two weeks' isolation is widely recommended for people commencing treatment for pulmonary tuberculosis (TB). The evidence that this corresponds to clearance of potentially infectious tuberculous mycobacteria in sputum is not well established. This World Health Organization-commissioned review investigated sputum sterilisation dynamics during TB treatment. METHODS AND FINDINGS: For the main analysis, 2 systematic literature searches of OvidSP MEDLINE, Embase, and Global Health, and EBSCO CINAHL Plus were conducted to identify studies with data on TB infectiousness (all studies to search date, 1 December 2017) and all randomised controlled trials (RCTs) for drug-susceptible TB (from 1 January 1990 to search date, 20 February 2018). Included articles reported on patients receiving effective treatment for culture-confirmed drug-susceptible pulmonary TB. The outcome of interest was sputum bacteriological conversion: the proportion of patients having converted by a defined time point or a summary measure of time to conversion, assessed by smear or culture. Any study design with 10 or more particpants was considered. Record sifting and data extraction were performed in duplicate. Random effects meta-analyses were performed. A narrative summary additionally describes the results of a systematic search for data evaluating infectiousness from humans to experimental animals (PubMed, all studies to 27 March 2018). Other evidence on duration of infectiousness-including studies reporting on cough dynamics, human tuberculin skin test conversion, or early bactericidal activity of TB treatments-was outside the scope of this review. The literature search was repeated on 22 November 2020, at the request of the editors, to identify studies published after the previous censor date. Four small studies reporting 3 different outcome measures were identified, which included no data that would alter the findings of the review; they are not included in the meta-analyses. Of 5,290 identified records, 44 were included. Twenty-seven (61%) were RCTs and 17 (39%) were cohort studies. Thirteen studies (30%) reported data from Africa, 12 (27%) from Asia, 6 (14%) from South America, 5 (11%) from North America, and 4 (9%) from Europe. Four studies reported data from multiple continents. Summary estimates suggested smear conversion in 9% of patients at 2 weeks (95% CI 3%-24%, 1 single study [N = 1]), and 82% of patients at 2 months of treatment (95% CI 78%-86%, N = 10). Among baseline smear-positive patients, solid culture conversion occurred by 2 weeks in 5% (95% CI 0%-14%, N = 2), increasing to 88% at 2 months (95% CI 84%-92%, N = 20). At equivalent time points, liquid culture conversion was achieved in 3% (95% CI 1%-16%, N = 1) and 59% (95% CI 47%-70%, N = 8). Significant heterogeneity was observed. Further interrogation of the data to explain this heterogeneity was limited by the lack of disaggregation of results, including by factors such as HIV status, baseline smear status, and the presence or absence of lung cavitation. CONCLUSIONS: This systematic review found that most patients remained culture positive at 2 weeks of TB treatment, challenging the view that individuals are not infectious after this interval. Culture positivity is, however, only 1 component of infectiousness, with reduced cough frequency and aerosol generation after TB treatment initiation likely to also be important. Studies that integrate our findings with data on cough dynamics could provide a more complete perspective on potential transmission of Mycobacterium tuberculosis by individuals on treatment. TRIAL REGISTRATION: Systematic review registration: PROSPERO 85226.

Impact of the Covid-19 epidemic and related social distancing regulations on social contact and SARS-CoV-2 transmission potential in rural South Africa: analysis of repeated cross-sectional surveys.

BACKGROUND: South Africa implemented rapid and strict physical distancing regulations to minimize SARS-CoV-2 epidemic spread. Evidence on the impact of such measures on interpersonal contact in rural and lower-income settings is limited. METHODS: We compared population-representative social contact surveys conducted in the same rural KwaZulu-Natal location once in 2019 and twice in mid-2020. Respondents reported characteristics of physical and conversational ('close interaction') contacts over 24 hours. We built age-mixing matrices and estimated the proportional change in the SARS-CoV-2 reproduction number (R0). Respondents also reported counts of others present at locations visited and transport used, from which we evaluated change in potential exposure to airborne infection due to shared indoor space ('shared air'). RESULTS: Respondents in March-December 2019 (n = 1704) reported a mean of 7.4 close interaction contacts and 196 shared air person-hours beyond their homes. Respondents in June-July 2020 (n = 216), as the epidemic peaked locally, reported 4.1 close interaction contacts and 21 shared air person-hours outside their home, with significant declines in others' homes and public spaces. Adults aged over 50 had fewer close contacts with others over 50, but little change in contact with 15-29 year olds, reflecting ongoing contact within multigenerational households. We estimate potential R0 fell by 42% (95% plausible range 14-59%) between 2019 and June-July 2020. CONCLUSIONS: Extra-household social contact fell substantially following imposition of Covid-19 distancing regulations in rural South Africa. Ongoing contact within intergenerational households highlighted a potential limitation of social distancing measures in protecting older adults.

The impact of COVID-19 control measures on social contacts and transmission in Kenyan informal settlements.

BACKGROUND: Many low- and middle-income countries have implemented control measures against coronavirus disease 2019 (COVID-19). However, it is not clear to what extent these measures explain the low numbers of recorded COVID-19 cases and deaths in Africa. One of the main aims of control measures is to reduce respiratory pathogen transmission through direct contact with others. In this study, we collect contact data from residents of informal settlements around Nairobi, Kenya, to assess if control measures have changed contact patterns, and estimate the impact of changes on the basic reproduction number (R0). METHODS: We conducted a social contact survey with 213 residents of five informal settlements around Nairobi in early May 2020, 4 weeks after the Kenyan government introduced enhanced physical distancing measures and a curfew between 7 pm and 5 am. Respondents were asked to report all direct physical and non-physical contacts made the previous day, alongside a questionnaire asking about the social and economic impact of COVID-19 and control measures. We examined contact patterns by demographic factors, including socioeconomic status. We described the impact of COVID-19 and control measures on income and food security. We compared contact patterns during control measures to patterns from non-pandemic periods to estimate the change in R0. RESULTS: We estimate that control measures reduced physical contacts by 62% and non-physical contacts by either 63% or 67%, depending on the pre-COVID-19 comparison matrix used. Masks were worn by at least one person in 92% of contacts. Respondents in the poorest socioeconomic quintile reported 1.5 times more contacts than those in the richest. Eighty-six percent of respondents reported a total or partial loss of income due to COVID-19, and 74% reported eating less or skipping meals due to having too little money for food. CONCLUSION: COVID-19 control measures have had a large impact on direct contacts and therefore transmission, but have also caused considerable economic and food insecurity. Reductions in R0 are consistent with the comparatively low epidemic growth in Kenya and other sub-Saharan African countries that implemented similar, early control measures. However, negative and inequitable impacts on economic and food security may mean control measures are not sustainable in the longer term.

Improving ART programme retention and viral suppression are key to maximising impact of treatment as prevention - a modelling study.

BACKGROUND: UNAIDS calls for fewer than 500,000 new HIV infections/year by 2020, with treatment-as-prevention being a key part of their strategy for achieving the target. A better understanding of the contribution to transmission of people at different stages of the care pathway can help focus intervention services at populations where they may have the greatest effect. We investigate this using Uganda as a case study. METHODS: An individual-based HIV/ART model was fitted using history matching. 100 model fits were generated to account for uncertainties in sexual behaviour, HIV epidemiology, and ART coverage up to 2015 in Uganda. A number of different ART scale-up intervention scenarios were simulated between 2016 and 2030. The incidence and proportion of transmission over time from people with primary infection, post-primary ART-naïve infection, and people currently or previously on ART was calculated. RESULTS: In all scenarios, the proportion of transmission by ART-naïve people decreases, from 70% (61%-79%) in 2015 to between 23% (15%-40%) and 47% (35%-61%) in 2030. The proportion of transmission by people on ART increases from 7.8% (3.5%-13%) to between 14% (7.0%-24%) and 38% (21%-55%). The proportion of transmission by ART dropouts increases from 22% (15%-33%) to between 31% (23%-43%) and 56% (43%-70%). CONCLUSIONS: People who are currently or previously on ART are likely to play an increasingly large role in transmission as ART coverage increases in Uganda. Improving retention on ART, and ensuring that people on ART remain virally suppressed, will be key in reducing HIV incidence in Uganda.

Universal test, treat, and keep: improving ART retention is key in cost-effective HIV control in Uganda.

BACKGROUND: With ambitious new UNAIDS targets to end AIDS by 2030, and new WHO treatment guidelines, there is increased interest in the best way to scale-up ART coverage. We investigate the cost-effectiveness of various ART scale-up options in Uganda. METHODS: Individual-based HIV/ART model of Uganda, calibrated using history matching. 22 ART scale-up strategies were simulated from 2016 to 2030, comprising different combinations of six single interventions (1. increased HIV testing rates, 2. no CD4 threshold for ART initiation, 3. improved ART retention, 4. increased ART restart rates, 5. improved linkage to care, 6. improved pre-ART care). The incremental net monetary benefit (NMB) of each intervention was calculated, for a wide range of different willingness/ability to pay (WTP) per DALY averted (health-service perspective, 3% discount rate). RESULTS: For all WTP thresholds above $210, interventions including removing the CD4 threshold were likely to be most cost-effective. At a WTP of $715 (1 × per-capita-GDP) interventions to improve linkage to and retention/re-enrolment in HIV care were highly likely to be more cost-effective than interventions to increase rates of HIV testing. At higher WTP (> ~ $1690), the most cost-effective option was 'Universal Test, Treat, and Keep' (UTTK), which combines interventions 1-5 detailed above. CONCLUSIONS: Our results support new WHO guidelines to remove the CD4 threshold for ART initiation in Uganda. With additional resources, this could be supplemented with interventions aimed at improving linkage to and/or retention in HIV care. To achieve the greatest reductions in HIV incidence, a UTTK policy should be implemented.

Bayesian history matching of complex infectious disease models using emulation: a tutorial and a case study on HIV in Uganda.

Advances in scientific computing have allowed the development of complex models that are being routinely applied to problems in disease epidemiology, public health and decision making. The utility of these models depends in part on how well they can reproduce empirical data. However, fitting such models to real world data is greatly hindered both by large numbers of input and output parameters, and by long run times, such that many modelling studies lack a formal calibration methodology. We present a novel method that has the potential to improve the calibration of complex infectious disease models (hereafter called simulators). We present this in the form of a tutorial and a case study where we history match a dynamic, event-driven, individual-based stochastic HIV simulator, using extensive demographic, behavioural and epidemiological data available from Uganda. The tutorial describes history matching and emulation. History matching is an iterative procedure that reduces the simulator's input space by identifying and discarding areas that are unlikely to provide a good match to the empirical data. History matching relies on the computational efficiency of a Bayesian representation of the simulator, known as an emulator. Emulators mimic the simulator's behaviour, but are often several orders of magnitude faster to evaluate. In the case study, we use a 22 input simulator, fitting its 18 outputs simultaneously. After 9 iterations of history matching, a non-implausible region of the simulator input space was identified that was 10(11) times smaller than the original input space. Simulator evaluations made within this region were found to have a 65% probability of fitting all 18 outputs. History matching and emulation are useful additions to the toolbox of infectious disease modellers. Further research is required to explicitly address the stochastic nature of the simulator as well as to account for correlations between outputs.

Comparison of indoor contact time data in Zambia and Western Cape, South Africa suggests targeting of interventions to reduce Mycobacterium tuberculosis transmission should be informed by local data.

BACKGROUND: In high incidence settings, the majority of Mycobacterium tuberculosis (M.tb) transmission occurs outside the household. Little is known about where people's indoor contacts occur outside the household, and how this differs between different settings. We estimate the number of contact hours that occur between adults and adult/youths and children in different building types in urban areas in Western Cape, South Africa, and Zambia. METHODS: Data were collected from 3206 adults using a cross-sectional survey, on buildings visited in a 24-h period, including building function, visit duration, and number of adults/youths and children (5-12 years) present. The mean numbers of contact hours per day by building function were calculated. RESULTS: Adults in Western Cape were more likely to visit workplaces, and less likely to visit shops and churches than adults in Zambia. Adults in Western Cape spent longer per visit in other homes and workplaces than adults in Zambia. More adults/youths were present at visits to shops and churches in Western Cape than in Zambia, and fewer at homes and hairdressers. More children were present at visits to shops in Western Cape than in Zambia, and fewer at schools and hairdressers. Overall numbers of adult/youth indoor contact hours were the same at both sites (35.4 and 37.6 h in Western Cape and Zambia respectively, p = 0.4). Child contact hours were higher in Zambia (16.0 vs 13.7 h, p = 0.03). Adult/youth and child contact hours were highest in workplaces in Western Cape and churches in Zambia. Compared to Zambia, adult contact hours in Western Cape were higher in workplaces (15.2 vs 8.0 h, p = 0.004), and lower in churches (3.7 vs 8.6 h, p = 0.002). Child contact hours were higher in other peoples' homes (2.8 vs 1.6 h, p = 0.03) and workplaces (4.9 vs 2.1 h, p = 0.003), and lower in churches (2.5 vs 6.2, p = 0.004) and schools (0.4 vs 1.5, p = 0.01). CONCLUSIONS: Patterns of indoor contact between adults and adults/youths and children differ between different sites in high M.tb incidence areas. Targeting public buildings with interventions to reduce M.tb transmission (e.g. increasing ventilation or UV irradiation) should be informed by local data.

Qualitative system dynamics modelling to support the design and implementation of tuberculosis infection prevention and control measures in South African primary health care facilities.

Tuberculosis infection prevention and control (TB IPC) measures are a cornerstone of policy, but measures are diverse and variably implemented. Limited attention has been paid to the health system environment which influences successful implementation of these measures. We used qualitative system dynamics and group-model-building methods 1) develop a qualitative causal map of the interlinked drivers of Mycobacterium tuberculosis (Mtb) transmission in South African primary health care facilities which in turn, helped us to 2) identify plausible IPC interventions to reduce risk of transmission. Two one-day participatory workshops were held in 2019 with policy- and decision-makers at national and provincial level, and patient advocates and health professionals at clinic and district level. Causal loop diagrams were generated by participants and combined by investigators. The research team reviewed diagrams to identify the drivers of nosocomial transmission of Mtb in primary health care facilities. Interventions proposed by participants were mapped onto diagrams to identify anticipated mechanisms of action and effect. Three systemic drivers were identified: 1) Mtb nosocomial transmission is driven by bottlenecks in patient flow at given times; 2) IPC implementation and clinic processes are anchored within a staff "culture of nominal compliance"; and 3) limited systems-learning at policy level inhibits effective clinic management and IPC implementation. Interventions prioritised by workshop participants included infrastructural, organisational, and behavioural strategies that target three areas: 1) improve air quality; 2) improve use of personal protective equipment; and 3) reduce the number of individuals in the clinic. In addition to core mechanisms, participants elaborated specific additional enablers that would help sustain implementation. Qualitative system dynamics modelling (SDM) methods allowed us to capture stakeholder views and potential solutions to address the problem of sub-optimal TB IPC implementation. The participatory elements of SDM facilitated problem-solving and inclusion of multiple factors frequently neglected when considering implementation.

Cost-effectiveness of tuberculosis infection prevention and control interventions in South African clinics: a model-based economic evaluation informed by complexity science methods.

INTRODUCTION: Nosocomial Mycobacterium tuberculosis (Mtb) transmission substantially impacts health workers, patients and communities. Guidelines for tuberculosis infection prevention and control (TB IPC) exist but implementation in many settings remains suboptimal. Evidence is needed on cost-effective investments to prevent Mtb transmission that are feasible in routine clinic environments. METHODS: A set of TB IPC interventions was codesigned with local stakeholders using system dynamics modelling techniques that addressed both core activities and enabling actions to support implementation. An economic evaluation of these interventions was conducted at two clinics in KwaZulu-Natal, employing agent-based models of Mtb transmission within the clinics and in their catchment populations. Intervention costs included the costs of the enablers (eg, strengthened supervision, community sensitisation) identified by stakeholders to ensure uptake and adherence. RESULTS: All intervention scenarios modelled, inclusive of the relevant enablers, cost less than US$200 per disability-adjusted life-year (DALY) averted and were very cost-effective in comparison to South Africa's opportunity cost-based threshold (US$3200 per DALY averted). Two interventions, building modifications to improve ventilation and maximising use of the existing Central Chronic Medicines Dispensing and Distribution system to reduce the number of clinic attendees, were found to be cost saving over the 10-year model time horizon. Incremental cost-effectiveness ratios were sensitive to assumptions on baseline clinic ventilation rates, the prevalence of infectious TB in clinic attendees and future HIV incidence but remained highly cost-effective under all uncertainty analysis scenarios. CONCLUSION: TB IPC interventions in clinics, including the enabling actions to ensure their feasibility, afford very good value for money and should be prioritised for implementation within the South African health system.

Is neglect of self-clearance biasing TB vaccine impact estimates?

BACKGROUND: Mathematical modelling has been used extensively to estimate the potential impact of new tuberculosis vaccines, with the majority of existing models assuming that individuals with Mycobacterium tuberculosis (Mtb) infection remain at lifelong risk of tuberculosis disease. Recent research provides evidence that self-clearance of Mtb infection may be common, which may affect the potential impact of new vaccines that only take in infected or uninfected individuals. We explored how the inclusion of self-clearance in models of tuberculosis affects the estimates of vaccine impact in China and India. METHODS: For both countries, we calibrated a tuberculosis model to a scenario without self-clearance and to various scenarios with self-clearance. To account for the current uncertainty in self-clearance properties, we varied the rate of self-clearance, and the level of protection against reinfection in self-cleared individuals. We introduced potential new vaccines in 2025, exploring vaccines that work in uninfected or infected individuals only, or that are effective regardless of infection status, and modelling scenarios with different levels of vaccine efficacy in self-cleared individuals. We then estimated the relative disease incidence reduction in 2050 for each vaccine compared with the no vaccination scenario. FINDINGS: The inclusion of self-clearance increased the estimated relative reductions in incidence in 2050 for vaccines effective only in uninfected individuals, by a maximum of 12% in China and 8% in India. The inclusion of self-clearance increased the estimated impact of vaccines only effective in infected individuals in some scenarios and decreased it in others, by a maximum of 14% in China and 15% in India. As would be expected, the inclusion of self-clearance had minimal impact on estimated reductions in incidence for vaccines that work regardless of infection status. INTERPRETATIONS: Our work suggests that the neglect of self-clearance in mathematical models of tuberculosis vaccines does not result in substantially biased estimates of tuberculosis vaccine impact. It may, however, mean that we are slightly underestimating the relative advantages of vaccines that work in uninfected individuals only compared with those that work in infected individuals.

Is neglect of self-clearance biassing TB vaccine impact estimates?

Background: Mathematical modelling has been used extensively to estimate the potential impact of new tuberculosis vaccines, with the majority of existing models assuming that individuals with Mycobacterium tuberculosis (Mtb) infection remain at lifelong risk of tuberculosis disease. Recent research provides evidence that self-clearance of Mtb infection may be common, which may affect the potential impact of new vaccines that only take in infected or uninfected individuals. We explored how the inclusion of self-clearance in models of tuberculosis affects the estimates of vaccine impact in China and India. Methods: For both countries, we calibrated a tuberculosis model to a scenario without self-clearance and to various scenarios with self-clearance. To account for the current uncertainty in self-clearance properties, we varied the rate of self-clearance, and the level of protection against reinfection in self-cleared individuals. We introduced potential new vaccines in 2025, exploring vaccines that work in uninfected or infected individuals only, or that are effective regardless of infection status, and modelling scenarios with different levels of vaccine efficacy in self-cleared individuals. We then estimated the relative incidence reduction in 2050 for each vaccine compared to the no vaccination scenario. Findings: The inclusion of self-clearance increased the estimated relative reductions in incidence in 2050 for vaccines effective only in uninfected individuals, by a maximum of 12% in China and 8% in India. The inclusion of self-clearance increased the estimated impact of vaccines only effective in infected individuals in some scenarios and decreased it in others, by a maximum of 14% in China and 15% in India. As would be expected, the inclusion of self-clearance had minimal impact on estimated reductions in incidence for vaccines that work regardless of infection status. Interpretations: Our work suggests that the neglect of self-clearance in mathematical models of tuberculosis vaccines does not result in substantially biased estimates of tuberculosis vaccine impact. It may, however, mean that we are slightly underestimating the relative advantages of vaccines that work in uninfected individuals only compared to those that work in infected individuals.

Demonstrating multi-country calibration of a tuberculosis model using new history matching and emulation package - hmer.

Infectious disease models are widely used by epidemiologists to improve the understanding of transmission dynamics and disease natural history, and to predict the possible effects of interventions. As the complexity of such models increases, however, it becomes increasingly challenging to robustly calibrate them to empirical data. History matching with emulation is a calibration method that has been successfully applied to such models, but has not been widely used in epidemiology partly due to the lack of available software. To address this issue, we developed a new, user-friendly R package hmer to simply and efficiently perform history matching with emulation. In this paper, we demonstrate the first use of hmer for calibrating a complex deterministic model for the country-level implementation of tuberculosis vaccines to 115 low- and middle-income countries. The model was fit to 9-13 target measures, by varying 19-22 input parameters. Overall, 105 countries were successfully calibrated. Among the remaining countries, hmer visualisation tools, combined with derivative emulation methods, provided strong evidence that the models were misspecified and could not be calibrated to the target ranges. This work shows that hmer can be used to simply and rapidly calibrate a complex model to data from over 100 countries, making it a useful addition to the epidemiologist's calibration tool-kit.

Time to change the way we think about tuberculosis infection prevention and control in health facilities: insights from recent research.

In clinical settings where airborne pathogens, such as Mycobacterium tuberculosis, are prevalent, they constitute an important threat to health workers and people accessing healthcare. We report key insights from a 3-year project conducted in primary healthcare clinics in South Africa, alongside other recent tuberculosis infection prevention and control (TB-IPC) research. We discuss the fragmentation of TB-IPC policies and budgets; the characteristics of individuals attending clinics with prevalent pulmonary tuberculosis; clinic congestion and patient flow; clinic design and natural ventilation; and the facility-level determinants of the implementation (or not) of TB-IPC interventions. We present modeling studies that describe the contribution of M. tuberculosis transmission in clinics to the community tuberculosis burden and economic evaluations showing that TB-IPC interventions are highly cost-effective. We argue for a set of changes to TB-IPC, including better coordination of policymaking, clinic decongestion, changes to clinic design and building regulations, and budgeting for enablers to sustain implementation of TB-IPC interventions. Additional research is needed to find the most effective means of improving the implementation of TB-IPC interventions; to develop approaches to screening for prevalent pulmonary tuberculosis that do not rely on symptoms; and to identify groups of patients that can be seen in clinic less frequently.

Quantifying progression and regression across the spectrum of pulmonary tuberculosis: a data synthesis study.

BACKGROUND: Prevalence surveys show a substantial burden of subclinical (asymptomatic but infectious) tuberculosis, from which individuals can progress, regress, or even persist in a chronic disease state. We aimed to quantify these pathways across the spectrum of tuberculosis disease. METHODS: We created a deterministic framework of untreated tuberculosis disease with progression and regression between three states of pulmonary tuberculosis disease: minimal (non-infectious), subclinical (asymptomatic but infectious), and clinical (symptomatic and infectious). We obtained data from a previous systematic review of prospective and retrospective studies that followed and recorded the disease state of individuals with tuberculosis in a cohort without treatment. These data were considered in a Bayesian framework, enabling quantitative estimation of tuberculosis disease pathways with rates of transition between states and 95% uncertainty intervals (UIs). FINDINGS: We included 22 studies with data from 5942 individuals in our analysis. Our model showed that after 5 years, 40% (95% UI 31·3-48·0) of individuals with prevalent subclinical disease at baseline recover and 18% (13·3-24·0) die from tuberculosis, with 14% (9·9-19·2) still having infectious disease, and the remainder with minimal disease at risk of re-progression. Over 5 years, 50% (40·0-59·1) of individuals with subclinical disease at baseline never develop symptoms. For those with clinical disease at baseline, 46% (38·3-52·2) die and 20% (15·2-25·8) recover from tuberculosis, with the remainder being in or transitioning between the three disease states after 5 years. We estimated the 10-year mortality of people with untreated prevalent infectious tuberculosis to be 37% (30·5-45·4). INTERPRETATION: For people with subclinical tuberculosis, classic clinical disease is neither an inevitable nor an irreversible outcome. As such, reliance on symptom-based screening means a large proportion of people with infectious disease might never be detected. FUNDING: TB Modelling and Analysis Consortium and European Research Council.

Evaluation of respondent-driven sampling.

BACKGROUND: Respondent-driven sampling is a novel variant of link-tracing sampling for estimating the characteristics of hard-to-reach groups, such as HIV prevalence in sex workers. Despite its use by leading health organizations, the performance of this method in realistic situations is still largely unknown. We evaluated respondent-driven sampling by comparing estimates from a respondent-driven sampling survey with total population data. METHODS: Total population data on age, tribe, religion, socioeconomic status, sexual activity, and HIV status were available on a population of 2402 male household heads from an open cohort in rural Uganda. A respondent-driven sampling (RDS) survey was carried out in this population, using current methods of sampling (RDS sample) and statistical inference (RDS estimates). Analyses were carried out for the full RDS sample and then repeated for the first 250 recruits (small sample). RESULTS: We recruited 927 household heads. Full and small RDS samples were largely representative of the total population, but both samples underrepresented men who were younger, of higher socioeconomic status, and with unknown sexual activity and HIV status. Respondent-driven sampling statistical inference methods failed to reduce these biases. Only 31%-37% (depending on method and sample size) of RDS estimates were closer to the true population proportions than the RDS sample proportions. Only 50%-74% of respondent-driven sampling bootstrap 95% confidence intervals included the population proportion. CONCLUSIONS: Respondent-driven sampling produced a generally representative sample of this well-connected nonhidden population. However, current respondent-driven sampling inference methods failed to reduce bias when it occurred. Whether the data required to remove bias and measure precision can be collected in a respondent-driven sampling survey is unresolved. Respondent-driven sampling should be regarded as a (potentially superior) form of convenience sampling method, and caution is required when interpreting findings based on the sampling method.

Exploring the potential impact of a reduction in partnership concurrency on HIV incidence in rural Uganda: a modeling study.

BACKGROUND: A number of African countries have planned campaigns against concurrency. It will not be possible to separate the effects of a reduction in concurrency from other behavior changes when evaluating these campaigns. This modeling study explores the potential impact of an intervention to reduce partnership concurrency on HIV incidence in contemporary rural Uganda, keeping incidence of sex acts and partnerships in the population constant. METHODS: Data on demography, sexual behavior, and HIV prevalence from Uganda were used to parameterize an individual-based HIV transmission model. Three baseline model scenarios were simulated, representing the best estimate of concurrency prevalence in this population, and low and high plausible bounds. Interventions that reduced concurrency by 20% and 50% between 2010 and 2020 were simulated, and the impact on HIV incidence in 2020 was calculated. RESULTS: Data showed 9.6% (7.9%-11.4%) of men and 0.2% (0.0%-0.4%) of women reported concurrency in 2008. Reducing concurrency had a nonlinear impact on HIV incidence. A 20% reduction in concurrency reduced HIV incidence by 4.1% (0.3%-5.7%) in men and 9.2% (2.1%-16.8%) in women; a 50% reduction in concurrency reduced HIV incidence by 6.0% (1.4%-10.8%) in men and 16.2% (6.3%-23.4%) in women. CONCLUSIONS: Interventions against concurrency have the potential to reduce HIV incidence and may have a higher impact in women than in men. In rural Uganda, overall impact was modest, and this study does not provide strong support for the prioritization of concurrency as a target for behavior change interventions. However, it may be more useful in higher concurrency settings and for reducing HIV incidence in women.

Direct estimates of absolute ventilation and estimated Mycobacterium tuberculosis transmission risk in clinics in South Africa.

Healthcare facilities are important sites for the transmission of pathogens spread via bioaerosols, such as Mycobacterium tuberculosis. Natural ventilation can play an important role in reducing this transmission. We aimed to measure rates of natural ventilation in clinics in KwaZulu-Natal and Western Cape provinces, South Africa, then use these measurements to estimate Mycobacterium tuberculosis transmission risk. We measured ventilation in clinic spaces using a tracer-gas release method. In spaces where this was not possible, we estimated ventilation using data on indoor and outdoor carbon dioxide levels. Ventilation was measured i) under usual conditions and ii) with all windows and doors fully open. Under various assumptions about infectiousness and duration of exposure, measured absolute ventilation rates were related to risk of Mycobacterium tuberculosis transmission using the Wells-Riley Equation. In 2019, we obtained ventilation measurements in 33 clinical spaces in 10 clinics: 13 consultation rooms, 16 waiting areas and 4 other clinical spaces. Under usual conditions, the absolute ventilation rate was much higher in waiting rooms (median 1769 m3/hr, range 338-4815 m3/hr) than in consultation rooms (median 197 m3/hr, range 0-1451 m3/hr). When compared with usual conditions, fully opening existing doors and windows resulted in a median two-fold increase in ventilation. Using standard assumptions about infectiousness, we estimated that a health worker would have a 24.8% annual risk of becoming infected with Mycobacterium tuberculosis, and that a patient would have an 0.1% risk of becoming infected per visit. Opening existing doors and windows and rearranging patient pathways to preferentially use better ventilated clinic spaces result in important reductions in Mycobacterium tuberculosis transmission risk. However, unless combined with other tuberculosis infection prevention and control interventions, these changes are insufficient to reduce risk to health workers, and other highly exposed individuals, to acceptable levels.